OBJECTIVES: Novel approaches for the synthesis of peptides and proteins are proposed which take advantage of the covalent linkage of the peptide chain to new polymeric supports which allow the use of both aqueous and polar organic reaction media. In contrast to current standard Merrifield-type methods, we propose to investigate: 1) insoluble polymer supports which are compatible in their physico-chemical properties with the growing peptide chain, solvents and reagents, which, in fact, will enhance reactions by creating an environment more conducive to synthesis than free solution chemistry; 2) novel protecting groups for amino acids and new attaching links for the peptide to polymer, which will allow attachment and cleavage by the mildest reaction conditions (such as enzymatic, photolytic, or chemically distinct methods) rather than detachment by the harshest conditions as currently required for the last step of peptide synthesis; and 3) a general synthetic scheme based on bidirectional (a constituent amino acid residue is attached to the polymer via its side chain) fragment coupling directed toward the economical and convenient synthesis of peptides and proteins in aqueous media at approximately physiological pH and temperature.